The studies of the role of gamma-aminobutyric acid (GABA) system in the central nervous system in the development of morphine tolerance and physical dependence are investigated in the mouse. The research plan includes: (1) A study of the changes of the functional state of GABA in relation to the development of tolerance to and physical dependence on morphine by means of pharmacological tools; (2) A study of the role of neuronal and glial GABA systems involved in the mechanism of morphine tolerance and dependence; (3) A monitoring of the levels of GABA and two of its related enzymes, Glutamate decarboxylase and GABA-alpha-ketoglutarate transaminase, in the whole brain, various areas of the brain and neuronal and glial preparations from either whole brain or various areas of the brain during the development of morphine tolerance and after withdrawal; (4) A study of the dynamic state of GABA metabolism during the development of morphine tolerance and after withdrawal; and (5) A study of the possible interactions of the GABA system and other neurotransmitters involved in the development of tolerance and physical dependence. Hopefully, this will lead us to a better understanding of the mechanisms concerned with morphine tolerance and physical dependence and thus provide a more rational basis for the treatment of narcotic abuse in humans.